1H-pyrrolo[2,3-b]pyridine derivatives and related compounds as BCL-2 inhibitors for the treatment of neoplastic and autoimmune diseases

Abstract

The disclosure provides compounds of Formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (I) or N-oxide thereof, wherein Z, Q 1 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , g, k, m, n, s, v, j, L, Z 1 , and, W are defined herein. Also disclosed is a method for treating a neoplastic disease and autoimmune disease with these compounds.

What is claimed is: 
     
         1 . A compound of Formula (B), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (B) or N-oxide thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Q 4  is heterocycloalkyl; 
 Q 5  is phenyl or spiro heterocyclic; 
 each of R 1 , R 2 , R 5 , and R 7 , independently, is H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, OR a , SR a , alkyl-R a , NH(CH 2 ) p R a , C(O)R a , S(O)R a , SO 2 R a , C(O)OR a , OC(O)R a , NR b R c , C(O)N(R b )R c , N(R b )C(O)R c , —P(O)R b R c , -alkyl-P(O)R b R c , —S(O)(═N(R b ))R c , —N═S(O)R b R c , ═NR b , SO 2 N(R b )R c , or N(R b )SO 2 R c , in which said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more R d ; 
 each of R a , R b , R c  and R d , independently, is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, C(O)NHOH, C(O)OH, C(O)NH 2 , alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more R e ; 
 R e  is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; 
 two R 1  groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the two R 1  groups is optionally substituted with one or more R d ; 
 two R 2  groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the two R 2  groups is optionally substituted with one or more R d ; 
 two R 5  groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the two R 5  groups is optionally substituted with one or more R d ; 
 an R 8  group and an —Z 1 -L-R 9  group, taken together with the atoms to which they are attached, form a heterocycloalkyl or heterocycloalkenyl, in which said heterocycloalkyl or heterocycloalkenyl of the R8 and —Z1-L-R9 groups, is substituted with one or more optionally substituted heterocycloalkyl or alkyl substituted by one optionally substituted heterocycloalkyl; 
 an R b  group and an R c  group, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the R b  and R c  groups, is optionally substituted with one or more R e ; 
 two R d  groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl, or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the two R d  groups is optionally substituted with one or more R e ; 
 two R e  groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl, in which said cycloalkyl or heterocycloalkyl of the two R e  groups is optionally substituted with one or more groups selected from H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; 
 g is 0, 1, 2, or 3; 
 each of n, v and k is, independently, 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
 each of m, p, and q is, independently, 0, 1, 2, 3, 4, or 5; and 
 f is 0, 1, or 2; and Z 2  is O, S, or S(O 2 ). 
 
     
     
         2 . The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (C-1) or Formula (C-2): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (D-1) or Formula (D-2): 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3, 4, 5, 6, or 7. 
       
     
     
         4 . The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is
 4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-(morpholinomethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide; 
 4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide; 
 N-((3-(1,4-dioxan-2-yl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; or 
 4-(2-(2-(2-cyclopropylphenyl)-4-methylpiperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-((R)-3-methyl-2,3-dihydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazin-1(6H)-yl)-N-((5-nitro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide. 
 
     
     
         5 . A pharmaceutical composition comprising a compound of Formula (B) or an N-oxide thereof as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (B) or an N-oxide thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
         6 . A method of treating a neoplastic disease, an autoimmune disease, or a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (B) or an N-oxide thereof as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (B) or an N-oxide thereof.